Safety and Efficacy of Infliximab and Corticosteroid Therapy in Checkpoint Inhibitor-induced Colitis

Emilie Kristine Dahl; Osama Karim Abed; Jens Kjeldsen; Marco Donia; Inge Marie Svane; Anders Dige; Jørgen Steen Agnholt; Jacob Tveiten Bjerrum; Jakob Benedict Seidelin

Disclosures

Aliment Pharmacol Ther. 2022;56(9):1370-1382. 

In This Article

Abstract and Introduction

Abstract

Background: Cancer patients treated with immune check point inhibitors are at risk of developing severe colitis. However, the efficacy and safety of treatment of severe colitis is poorly understood.

Aims: To explore the safety and efficacy of infliximab and corticosteroids in severe immune-mediated enterocolitis (IMC)

Method: We performed a nationwide retrospective cohort study on 140 cancer patients treated with infliximab due to IMC in Denmark from 2011 to 2021.

Results: The rate of complete remission with infliximab was 52% after one dose, increasing to 73% after two or more doses. Thirteen patients (10%) required additional treatment with vedolizumab. Patients were heavily exposed to corticosteroids and received a median accumulated dose of 3978 mg (interquartile range [IQR] 2552–6414). Age- and cancer-adjusted Cox regression analysis found that a high dose of prednisolone at start of tapering ≥75 mg/day was associated with increased mortality (HR 1.67, 1.04–2.69, p = 0.035). Patients responding to infliximab experienced an improvement of symptoms after 3 days (IQR 2–4) and complete remission after 31 days (IQR 14–61). Twenty-four percent required hospitalisation for infection during treatment for IMC, lasting 7 days (median). Secondary gastrointestinal infections occurred in 16%, with Clostridioides difficile being most common (64%). Further, 10% had a thromboembolic event during the first 90 days after infliximab treatment.

Conclusions: Infliximab led to complete resolution of symptoms in 73% of patients with IMC. High prednisolone dose at tapering was associated with increased mortality rate and a high incidence of infections and hospitalisations in patients with severe IMC. We suggest optimised infliximab treatment before escalation of steroid doses.

Introduction

Immune checkpoint inhibitors (ICI) have revolutionised the field of oncology within the last decade. ICI work by unleashing the T-cell arm of the adaptive immune system, leading to the immune-mediated attack of cancer cells. A common trade-off of a highly activated immune system is the occurrence of inflammatory side effects, or immune-related adverse events (irAE). Any organ can be affected, but the gastrointestinal tract appears to be the most commonly involved organ.[1] Immune-mediated enterocolitis (IMC) is often severe, and occasionally a life-threatening complication to the treatment with ICI.[2] Based on empirical evidence, most professional guidelines[3] recommend treatment with high doses of corticosteroids, with or without secondary immune-suppressive drugs, to mitigate severe IMC. Infliximab (IFX) is the most commonly recommended rescue treatment in corticosteroid-resistant IMC, with an efficacy of 81% in IMC.[4] However, little is known about the frequency of the side effects of drugs administered to alleviate severe IMC.

Inflammatory bowel diseases (IBD), such as Crohn's disease and ulcerative colitis, have some similarities to IMC both endoscopically and symptomatically.[5] In IBD patients hospitalised with a disease flare, the risk of a thromboembolic event is 2.85 times higher than in hospitalised patients without IBD.[6–8] Therefore, thromboembolic prophylaxis is recommended at hospitalisation during an IBD flare.[9–12] The recommendation for thromboembolic prophylaxis at hospitalisation for IMC remains unclear, it is recommended in the British guideline[13] but is not considered elsewhere.[14,15] The overall rate of thromboembolic events during treatment with ICI is reported to be 2.7%.[16] It is unknown whether treatment with corticosteroids and IFX affect or are associated with and increased risk of thromboembolic events in patients with severe IMC. In addition, the rate of serious infections during treatment with ICI in melanoma patients is reported to be 2%, and when corticosteroids or IFX are added the rate increases to 14%.[17] In IBD patients, corticosteroids are associated with a threefold increase in the risk of Clostridioides difficile infection compared with IFX.[18] The risk of C. difficile infection in severe IMC is not known.

Current guidelines describe no clear optimal strategy for the administration of IFX. One trial showed that early IFX initiation before day 10 resulted in a shorter hospital stay and shorter symptom duration,[19] yet other studies have not confirmed this finding.[5] Recently, it is debated if IFX have an impact on mortality as one study points in this direction, whereas others do not.[20]

Therefore, we aimed to investigate the impact of the duration and doses of IFX alongside the risk of common side effects to corticosteroids and IFX and to explore mortality related to IMC within a nationwide real-world cohort.

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